Short bowel syndrome (SBS) often requires parenteral nutrition (PN). The long term objective is to understand the mechanisms by which enteral and parenteral nutrients stimulate the neuroendocrine system to produce functional adaptation to bowel resection. Aims 1 &2 will use well-characterized resection models that show differential mucosal growth in response to luminal nutrients and endogenous levels of GLP-2. Aims 1 &2 will test the hypothesis that the ability of luminal nutrients to stimulate intestinal adaptation is dependent on vagal afferent innervation and the intestinotrophic actions of glucagon-like peptide 2 (GLP-2) and insulin-like growth factor I (IGF-I). Studies will be performed in rats using a "physiologic" resection model (Aim 1, 70% jejuno-ileal resection) and a "clinical" resection model that mimics human SBS (Aim 2, 60% jejuno-ileal resection + cecectomy), and varying levels of enteral and parenteral nutrients. We will determine if the intestinotrophic response to GLP-2 infusion is reduced by functional ablation of vagal afferents in association with reduced GLP-2 and IGF-I responses. Activation of vagal neurons in the brainstem will be assessed by quantification of neurons expressing c-Fos. Intestinal adaptive growth will be assessed by changes in cellularity, structure and ion transport function. GLP-2 receptors will be localized in residual bowel by IHC using an antibody specific for the GLP-2 receptor. The relative abundance of proglucagon, GLP-2 receptor, IGF-I, IGF binding protein (IGFBP) -3 and -5 mRNAs will be determined by quantitative PCR or RNase protection assay, in some cases after laser capture microdissection. Aim 3 will test the hypothesis that the final common pathway mediating resection-induced growth is IGF-I. We will establish primary cultures of subepithelial myofibroblasts from residual bowel of resected and transected rats to test in vitro how GLP-2 treatment affects expression of IGF-I and IGFBPs. Aim 3 will also use knock out mice with deletion of IGFBP-3 and -5 to determine if mucosal hyperplasia induced by coinfusion of IGF-I and GLP-2 with PN solution is dependent on increased expression of IGFBP -3 and -5. Public Health: This proposal seeks to improve treatment for SBS by better understanding how food and growth factors promote recovery of the gut with the goal of reducing dependence on intravenous feeding. New therapies would reduce health care costs and improve well-being for approximately 30,000 Americans with SBS.